Fungal blood stream infections are a serious problem with high morbidity and mortality. Blood stream infections from Candida albicans (among the most common), for example, often result from delayed or untreated local infections principally associated with the oral cavity, implants, surgical wounds, and the urinary tract. Fungal blood stream infections are dangerous and burdensome due to lengthened hospital stays, the need for expensive antifungal drugs, and high mortality rates (up to 40% for C. albicans). Furthermore, some of the most effective antifungal drugs exhibit serious side effects, including toxicity. Worldwide, fungal infections from pathogenic and opportunistic species are on the rise.
One of the most effective antifungal drugs, Amphotericin B (Am B), exhibits high toxicity, limiting its use and effectiveness. Efforts to reduce toxicity have included encapsulating Am B in nanoparticles, such as micelles, liposomes, and others. For example, U.S. Pat. No. 8,268,357, filed by Ryan and Oda, discloses particles for delivering drugs and other agents, the particles comprising a lipid binding polypeptide, a lipid bilayer and a non-polypeptide bioactive agent, and processes for making them.
US20110256213, filed by Onyuksel and Rubinstein, discloses a method of decreasing drug toxicity through use of sterically stabilized micelles or liposomes.
US20100210575, filed by Kwon and Vakil, discloses antifungal compositions comprising a derivatized Amphotericin B component such as Amphotericin B prepared with PEG-DSPE, where DSPE is distearoyl phosphatidylethanolamine, and methods of making and using them.
US20110256213, filed by Onyuksel and Rubinstein, discloses use of sterically stabilized micellar and liposomal compositions for the reduction or neutralization of endo-, exo- and other toxins associated with fungal and other agents, where the compositions can comprise water-insoluble antifungal agents.
US20100210575, filed by Kwon and Vakil, discloses inter alia PEG-distearoyl phosphatidylethanolamine (DSPE)/cholesterol micelle formulations to solubilize an antifungal agent, Amphotericin B, in combination with at least a second antifungal agent.
US20100062969, also filed by Onyuksel and Rubinstein, discloses a method of correcting oligopeptide misfolding through use of sterically stabilized micelles comprising a hydrophilic polymer-conjugated lipid or sterically stabilized mixed micelles (SSMM) of a hydrophilic polymer-conjugated lipid and a water-insoluble lipid, an example of the former is distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000).
Each of the following cited patents, U.S. Pat No. 8,268,357, US20110256213, US20100210575, US20100062969, are hereby incorporated by reference in their entirety.
Passive delivery of Amphotericin B has been accomplished by solubilization of the drug in deoxycholate (Fungizone). This is also the most toxic form of the drug. More recent passive delivery formulations include lipid complexes from Sigma-Tau (Abelcet), colloidal dispersions from Three Rivers Pharmaceuticals (Amphotec), and liposomes from Gilead (AmBisome) and Lifecare Innovations (Fungisome). Some of these formulations reduce toxicity, but do not eliminate it. Other passive delivery formulations under development include micelles, block co-polymer micelles, nano-spheres, and others. In passive delivery, the serum concentration of drug (and drug carrier) must be high enough to permit diffusion of sufficient drug to the site of infection deep inside tissues to eliminate the infection.
A superior approach is the use of targeted delivery. In this strategy, the toxic drug is encapsulated in a vehicle whose surface is modified with an agent that has high affinity for the site of the disease, such as a fungal infection.
Targeted delivery results in the drug (and carrier) accumulating at the site of infection, driven by interaction between the targeting agent and its target site in the fungal organism. With our invention, high affinity binding of the targeting agent to chitin fungal components thermodynamically drives accumulation of the drug at the site of infection, against a concentration gradient (low serum concentration and high infection site concentration). This substantially reduces the amount of antifungal drug in the blood stream compared to that necessary in passive delivery, thereby permitting therapeutic, and even prophylactic, use of highly effective, but otherwise toxic, antifungal drugs